Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact

Neuroscience

  • 442 Articles
  • 7 Posts
  • ← Previous
  • 1
  • 2
  • 3
  • 4
  • …
  • 44
  • 45
  • Next →
Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion
Tingjun Chen, … , Shihui Wei, Long-Jun Wu
Tingjun Chen, … , Shihui Wei, Long-Jun Wu
Published June 22, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI134816.
View: Text | PDF

Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion

  • Text
  • PDF
Abstract

Neuromyelitis optica (NMO) is a severe inflammatory autoimmune CNS disorder triggered by binding of an IgG autoantibody to the aquaporin 4 (AQP4) water channel on astrocytes. Activation of cytolytic complement has been implicated as the major effector of tissue destruction that secondarily involves myelin. We investigated early precytolytic events in the evolving pathophysiology of NMO in mice by continuously infusing IgG (NMO patient serum–derived or AQP4-specific mouse monoclonal), without exogenous complement, into the spinal subarachnoid space. Motor impairment and sublytic NMO-compatible immunopathology were IgG dose dependent, AQP4 dependent, and, unexpectedly, microglia dependent. In vivo spinal cord imaging revealed a striking physical interaction between microglia and astrocytes that required signaling from astrocytes by the C3a fragment of their upregulated complement C3 protein. Astrocytes remained viable but lost AQP4. Previously unappreciated crosstalk between astrocytes and microglia involving early-activated CNS-intrinsic complement components and microglial C3a receptor signaling appears to be a critical driver of the precytolytic phase in the evolving NMO lesion, including initial motor impairment. Our results indicate that microglia merit consideration as a potential target for NMO therapeutic intervention.

Authors

Tingjun Chen, Vanda A. Lennon, Yong U. Liu, Dale B. Bosco, Yujiao Li, Min-Hee Yi, Jia Zhu, Shihui Wei, Long-Jun Wu

×

Tau is not necessary for amyloid-beta-induced synaptic and memory impairments
Daniela Puzzo, … , Paul E. Fraser, Ottavio Arancio
Daniela Puzzo, … , Paul E. Fraser, Ottavio Arancio
Published June 16, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI137040.
View: Text | PDF

Tau is not necessary for amyloid-beta-induced synaptic and memory impairments

  • Text
  • PDF
Abstract

The amyloid hypothesis posits that the amyloid-beta (Aβ) protein precedes and requires microtubule-associated protein tau in a sort of trigger-bullet mechanism leading to Alzheimer’s disease (AD) pathology. This sequence of events has become dogmatic in the AD field and is used to explain clinical trial failures due to a late start of the intervention when Aβ already activated tau. Here, using a multidisplinary approach combining molecular biological, biochemical, histopathological, electrophysiological and behavioral methods we demonstrated that tau suppression did not protect against Aβ-induced damage of long-term synaptic plasticity and memory, as well as amyloid deposition. Tau suppression could even unravel a defect in basal synaptic transmission in a mouse model of amyloid deposition. Similarly, tau suppression did not protect against exogenous oligomeric tau induced impairment of long-term synaptic plasticity and memory. The protective effect of tau suppression was, in turn, confined to short-term plasticity and memory. Taken together, our data suggest that therapies downstream of Aβ and tau together are more suitable to combat AD than therapies against one or the other alone.

Authors

Daniela Puzzo, Elentina K. Argyrousi, Agnieszka Staniszewski, Hong Zhang, Elisa Calcagno, Elisa Zuccarello, Erica Acquarone, Mauro Fà, Domenica Donatella Li Puma, Claudio Grassi, Luciano D'Adamio, Nicholas M. Kanaan, Paul E. Fraser, Ottavio Arancio

×

Impact of TREM2R47H variant on tau pathology-induced gliosis and neurodegeneration
Maud Gratuze, … , Jason D. Ulrich, David M. Holtzman
Maud Gratuze, … , Jason D. Ulrich, David M. Holtzman
Published June 16, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI138179.
View: Text | PDF

Impact of TREM2R47H variant on tau pathology-induced gliosis and neurodegeneration

  • Text
  • PDF
Abstract

Alzheimer’s disease (AD) is characterized by amyloid-β-containing plaques and neurofibrillary tangles composed of aggregated, hyperphosphorylated tau. Beyond tau and Aβ, evidence suggests that microglia play an important role in AD pathogenesis. Rare variants in the microglial-expressed triggering receptor expressed on myeloid cells 2 (TREM2) gene increase AD risk 2-4-fold. It is likely that these TREM2 variants increase AD risk by decreasing the response of microglia to Aβ and its local toxicity. However, neocortical Aβ pathology occurs many years before neocortical tau pathology in AD. Thus, it will be important to understand the role of TREM2 in the context of tauopathy. We investigated the impact of the AD-associated TREM2 variant (R47H) on tau-mediated neuropathology in the PS19 mouse model of tauopathy. We assessed PS19 mice expressing human TREM2CV (common variant) or human TREM2R47H. PS19-T2R47H mice had significantly attenuated brain atrophy and synapse loss versus PS19-T2CV mice. Gene expression analyses and CD68 immunostaining revealed attenuated microglial reactivity in PS19-T2R47H versus PS19-T2CV mice. There was also a decrease in phagocytosis of postsynaptic elements by microglia expressing TREM2R47H in the PS19 mice and in human AD brains. These findings suggest that impaired TREM2 signaling reduces microglia-mediated neurodegeneration in the setting of tauopathy.

Authors

Maud Gratuze, Cheryl E.G. Leyns, Andrew D. Sauerbeck, Marie-Kim St-Pierre, Monica Xiong, Nayeon Kim, Javier Remolina Serrano, Marie-Ève Tremblay, Terrance T. Kummer, Marco Colonna, Jason D. Ulrich, David M. Holtzman

×

Impaired hypocretin/orexin system alters responses to salient stimuli in obese male mice
Ying Tan, … , Tamas L. Horvath, Xiao-Bing Gao
Ying Tan, … , Tamas L. Horvath, Xiao-Bing Gao
Published June 9, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI130889.
View: Text | PDF

Impaired hypocretin/orexin system alters responses to salient stimuli in obese male mice

  • Text
  • PDF
Abstract

The brain has evolved in an environment where food sources are scarce and foraging for food is one of the major challenges for survival of the individual and species. Basic and clinical studies show that obesity/overnutrition leads to overwhelming changes in the brain in animals and humans. However, the exact mechanisms underlying the consequences of excessive energy intake are not well understood. Neurons expressing the neuropeptide hypocretin/orexin (Hcrt) in the lateral/perifonical hypothalamus (LH) are critical for homeostatic regulation, reward seeking, stress response, and cognitive functions. In this study, we examined adaptations in Hcrt cells regulating behavioral responses to salient stimuli in diet-induced obese mice. Our results demonstrated changes in primary cilia, synaptic transmission and plasticity, cellular responses to neurotransmitters necessary for reward seeking and stress responses in Hcrt neurons from obese mice. Activities of neuronal networks in the LH and hippocampus were impaired as a result of decreased hypocretinergic function. The weakened Hcrt system decreased reward seeking while altering responses to acute stress (stress coping strategy), which were reversed by selectively activating Hcrt cells with chemogenetics. Taken together, our data suggest that a deficiency in the Hcrt signaling may be a common cause of behavioral changes (such as lowered arousal, weakened reward seek and altered stress response) in obese animals.

Authors

Ying Tan, Fu Hang, Zhong-Wu Liu, Milan Stoiljkovic, Mingxing Wu, Yue Tu, Wenfei Han, Angela M. Lee, Craig Kelley, Mihaly Hajos, Lingeng Lu, Luis de Lecea, Ivan de Araujo, Marina Picciotto, Tamas L. Horvath, Xiao-Bing Gao

×

Maternal high-fat diet during lactation reprograms the dopaminergic circuitry in mice
R.N. Lippert, … , P. Kloppenburg, J.C. Brüning
R.N. Lippert, … , P. Kloppenburg, J.C. Brüning
Published June 8, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI134412.
View: Text | PDF

Maternal high-fat diet during lactation reprograms the dopaminergic circuitry in mice

  • Text
  • PDF
Abstract

The maternal perinatal environment modulates brain formation, and altered maternal nutrition has been linked to the development of metabolic and psychiatric disorders in the offspring. Here, we showed that maternal high-fat diet (HFD) feeding during lactation in mice elicits long-lasting changes in gene expression in the offspring’s dopaminergic circuitry. This translated into silencing of dopaminergic midbrain neurons, reduced connectivity to their downstream targets, and reduced stimulus-evoked dopamine (DA) release in the striatum. Despite the attenuated activity of DA midbrain neurons, offspring from mothers exposed to HFD feeding exhibited a sexually dimorphic expression of DA-related phenotypes, i.e., hyperlocomotion in males and increased intake of palatable food and sucrose in females. These phenotypes arose from concomitantly increased spontaneous activity of D1 medium spiny neurons (MSNs) and profoundly decreased D2 MSN projections. Overall, we have unraveled a fundamental restructuring of dopaminergic circuitries upon time-restricted altered maternal nutrition to induce persistent behavioral changes in the offspring.

Authors

R.N. Lippert, S. Hess, P. Klemm, L.M. Burgeno, T. Jahans-Price, M.E. Walton, P. Kloppenburg, J.C. Brüning

×

Tentonin 3/TMEM150C senses blood pressure changes in the aortic arch
Huan-Jun Lu, … , Mi-Ock Lee, Uhtaek Oh
Huan-Jun Lu, … , Mi-Ock Lee, Uhtaek Oh
Published June 2, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI133798.
View: Text | PDF

Tentonin 3/TMEM150C senses blood pressure changes in the aortic arch

  • Text
  • PDF
Abstract

The baroreceptor reflex is a powerful neural feedback that regulates arterial pressure (AP). Mechanosensitive channels transduce pulsatile AP to electrical signals in baroreceptors. Here we show that tentonin 3 (TTN3/TMEM150C), a cation channel activated by mechanical strokes, is essential for detecting AP changes in the aortic arch. TTN3 was expressed in nerve terminals in the aortic arch and nodose ganglion (NG) neurons. Genetic ablation of Ttn3 induced ambient hypertension, tachycardia, AP fluctuations, and impaired baroreflex sensitivity. Chemogenetic silencing or activation of Ttn3+ neurons in the NG resulted in an increase in AP and heart rate, or vice versa. More important, overexpression of Ttn3 in the NG of Ttn3–/– mice reversed the cardiovascular changes observed in Ttn3–/– mice. We conclude that TTN3 is a molecular component contributing to the sensing of dynamic AP changes in baroreceptors.

Authors

Huan-Jun Lu, Thien-Luan Nguyen, Gyu-Sang Hong, Sungmin Pak, Hyesu Kim, Hyungsup Kim, Dong-Yoon Kim, Sung-Yon Kim, Yiming Shen, Pan Dong Ryu, Mi-Ock Lee, Uhtaek Oh

×

PD-1 blockade inhibits osteoclast formation and murine bone cancer pain
Kaiyuan Wang, … , Matthew J. Hilton, Ru-Rong Ji
Kaiyuan Wang, … , Matthew J. Hilton, Ru-Rong Ji
Published June 2, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI133334.
View: Text | PDF

PD-1 blockade inhibits osteoclast formation and murine bone cancer pain

  • Text
  • PDF
Abstract

Emerging immune therapy, such as with the anti–programmed cell death–1 (anti–PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 (Pd1−/−) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, Pd1−/− mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in Pd1−/− mice. Consistently, these beneficial effects in Pd1−/− mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti–PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.

Authors

Kaiyuan Wang, Yun Gu, Yihan Liao, Sangsu Bang, Christopher R. Donnelly, Ouyang Chen, Xueshu Tao, Anthony J. Mirando, Matthew J. Hilton, Ru-Rong Ji

×

Caspase-11–mediated enteric neuronal pyroptosis underlies Western diet–induced colonic dysmotility
Lan Ye, … , Wenhui Hu, Shanthi Srinivasan
Lan Ye, … , Wenhui Hu, Shanthi Srinivasan
Published June 2, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI130176.
View: Text | PDF

Caspase-11–mediated enteric neuronal pyroptosis underlies Western diet–induced colonic dysmotility

  • Text
  • PDF
Abstract

Enteric neuronal degeneration, as seen in inflammatory bowel disease, obesity, and diabetes, can lead to gastrointestinal dysmotility. Pyroptosis is a novel form of programmed cell death but little is known about its role in enteric neuronal degeneration. We observed higher levels of cleaved caspase-1, a marker of pyroptosis, in myenteric ganglia of overweight and obese human subjects compared with normal-weight subjects. Western diet–fed (WD-fed) mice exhibited increased myenteric neuronal pyroptosis, delayed colonic transit, and impaired electric field stimulation–induced colonic relaxation responses. WD increased TLR4 expression and cleaved caspase-1 in myenteric nitrergic neurons. Overactivation of nitrergic neuronal NF-κB signaling resulted in increased pyroptosis and delayed colonic motility. In caspase-11–deficient mice, WD did not induce nitrergic myenteric neuronal pyroptosis and colonic dysmotility. To understand the contributions of saturated fatty acids and bacterial products to the steps leading to enteric neurodegeneration, we performed in vitro experiments using mouse enteric neurons. Palmitate and lipopolysaccharide (LPS) increased nitrergic, but not cholinergic, enteric neuronal pyroptosis. LPS gained entry to the cytosol in the presence of palmitate, activating caspase-11 and gasdermin D, leading to pyroptosis. These results support a role of the caspase-11–mediated pyroptotic pathway in WD-induced myenteric nitrergic neuronal degeneration and colonic dysmotility, providing important therapeutic targets for enteric neuropathy.

Authors

Lan Ye, Ge Li, Anna Goebel, Abhinav V. Raju, Feng Kong, Yanfei Lv, Kailin Li, Yuanjun Zhu, Shreya Raja, Peijian He, Fang Li, Simon Musyoka Mwangi, Wenhui Hu, Shanthi Srinivasan

×

Posttranslational modifications define course of prion strain adaptation and disease phenotype
Natallia Makarava, … , Kara Molesworth, Ilia V. Baskakov
Natallia Makarava, … , Kara Molesworth, Ilia V. Baskakov
Published June 2, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI138677.
View: Text | PDF

Posttranslational modifications define course of prion strain adaptation and disease phenotype

  • Text
  • PDF
Abstract

Posttranslational modifications are a common feature of proteins associated with neurodegenerative diseases including prion protein (PrPC), tau and α-synuclein. Alternative self-propagating protein states or strains give rise to different disease phenotypes and display strain-specific subsets of posttranslational modifications. The relationships between strain-specific structure, posttranslational modifications and disease phenotype are poorly understood. We previously reported that among hundreds of PrPC sialoglycoforms expressed by a cell, individual prion strains recruited PrPC molecules selectively, according to the sialylation status of their N-linked glycans. Here we report that transmission of a prion strain to a new host is accompanied by a dramatic shift in the selectivity of recruitment of PrPC sialoglycoforms giving rise to PrPSc with a unique sialoglycoform signature and disease phenotype. The newly emerged strain has the shortest incubation time to disease, is characterized by a colocalization of PrPSc with microglia and a very profound proinflammatory response, features that are linked to a unique sialoglycoform composition of PrPSc. The current work provides experimental support for a hypothesis that strain-specific patterns of PrPSc sialoglycoforms formed as a result of selective recruitment dictate strain-specific disease phenotypes. This work suggests a causative relationship between a strain-specific structure, posttranslational modifications and disease phenotype.

Authors

Natallia Makarava, Jennifer Chen-Yu Chang, Kara Molesworth, Ilia V. Baskakov

×

Neuronal uptake transporters contribute to oxaliplatin neurotoxicity in mice
Kevin M. Huang, … , Shuiying Hu, Alex Sparreboom
Kevin M. Huang, … , Shuiying Hu, Alex Sparreboom
Published June 2, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI136796.
View: Text | PDF

Neuronal uptake transporters contribute to oxaliplatin neurotoxicity in mice

  • Text
  • PDF
Abstract

Peripheral neurotoxicity is a debilitating toxicity that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance of various solute carriers to the toxicity of anticancer drugs, the contribution of these proteins to oxaliplatin-induced peripheral neurotoxicity remains controversial. Among candidate transporters investigated in genetically-engineered mouse models, we provide evidence for a critical role of the organic cation transporter 2 (OCT2) in satellite glial cells to oxaliplatin-induced neurotoxicity, and demonstrate that targeting OCT2 using genetic and pharmacological approaches ameliorates acute and chronic forms of neurotoxicity. The relevance of this transport system was verified in transporter-deficient rats as a secondary model organism, and translational significance of preventative strategies was demonstrated in preclinical models of colorectal cancer. These studies suggest that pharmacological targeting of OCT2 could be exploited to afford neuroprotection in cancer patients requiring treatment with oxaliplatin.

Authors

Kevin M. Huang, Alix F. Leblanc, Muhammad Erfan Uddin, Ji Young Kim, Mingqing Chen, Eric D. Eisenmann, Alice Gibson, Yang Li, Kristen W. Hong, Duncan DiGiacomo, Sherry Huinan Xia, Paola Alberti, Alessia Chiorazzi, Stephen N. Housley, Timothy C. Cope, Jason A. Sprowl, Jing Wang, Charles L. Loprinzi, Anne Noonan, Maryam Lustberg, Guido Cavaletti, Navjotsingh Pabla, Shuiying Hu, Alex Sparreboom

×
  • ← Previous
  • 1
  • 2
  • 3
  • 4
  • …
  • 44
  • 45
  • Next →
DREAM suppression in Huntington’s disease
José Naranjo and colleagues reveal that downregulation of DREAM mediates derepression of ATF6, and this elevation of ATF6 plays an early neuroprotective role in Huntington’s disease…
Published January 11, 2016
Scientific Show StopperNeuroscience

Extra-cerebellar motor symptoms in Angelman’s syndrome
Caroline Bruinsma and colleagues evaluated cerebellar involvement in Angelman’s Syndrome motor deficits…
Published October 20, 2015
Scientific Show StopperNeuroscience

An epigenetic intervention for neurodegenerative diseases
Eva Benito and colleagues demonstrate that SAHA, a histone-deacetylase inhibitor, improves spatial memory and selectively regulates the neuronal epigenome in a mouse model of neurodegeneration…
Published August 17, 2015
Scientific Show StopperNeuroscience

Genetic and environmental interactions in Parkinson’s disease
Alevtina Zharikov and colleagues reveal that interplay between α-synuclein and environmental toxin exposure influences parkinsonian neurodegeneration…
Published June 15, 2015
Scientific Show StopperNeuroscience

TREM2 keeps myelinated axons under wraps
Pietro Poliani, Yaming Wang, and colleagues demonstrate that TREM2 deficiency reduces age-associated expansion of microglia and microglia-dependent remyelination…
Published April 20, 2015
Scientific Show StopperNeuroscience

Synergy among Parkinson’s disease-associated genes
Durga Meka and colleagues demonstrate that crosstalk between parkin and RET maintains mitochondrial integrity and protects dopaminergic neurons…
Published March 30, 2015
Scientific Show StopperNeuroscience

A model of periventricular leukomalacia
Tamar Licht, Talia Dor-Wollman and colleagues demonstrate that specific vulnerability of immature blood vessels surrounding ventricles predisposes to hypoxia-induced periventricular leukomalacia…
Published February 17, 2015
Scientific Show StopperNeuroscience
Advertisement
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts